Gut microbes release cancer-fighting bile acids that block hormone signals (Apr 2025) Microbiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity Other

[Michael Harrop]

https://medicalxpress.com/news/2025-04-gut-microbes-cancer-bile-acids.html
https://www.cell.com/cell/abstract/S0092-8674(25)00256-9

Bacteria naturally present in the human intestine (known as the gut microbiota) can transform cholesterol-derived bile acids into powerful metabolites that strengthen anti-cancer immunity by blocking androgen signaling

"I was very surprised by our findings. As far as I know, no one has previously discovered molecules like these bile acids that can interact with the androgen receptor in this way," said co-senior author Dr. Chun-Jun Guo

"We discovered more than 50 different bile acid molecules modified by the microbiota—many of which had never been identified before,"

Given that bile acids share the same steroid backbone as sex hormones like testosterone and estrogen, the structural resemblance raised an intriguing question for the researchers: could these microbially modified bile acids also interact with sex hormone receptors in the body?

Surprisingly, the answer appears to be yes.

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Highlights​

• Functional characterization of bile acid (BA) hydroxysteroid dehydrogenases
• Identification of microbiota-derived BA antagonists of host androgen receptor (AR)
• AR-antagonizing BA inhibits tumor progression via CD8+ T cell-intrinsic AR
• AR-antagonizing BA promotes CD8+ T cell stemness

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Summary​

Microbiota-derived bile acids (BAs) are associated with host biology/disease, yet their causal effects remain largely undefined. Herein, we speculate that characterizing previously undefined microbiota-derived BAs would uncover previously unknown BA-sensing receptors and their biological functions.

We integrated BA metabolomics and microbial genetics to functionally profile >200 putative microbiota BA metabolic genes. We identified 56 less-characterized BAs, many of which are detected in humans/mammals. Notably, a subset of these BAs are potent antagonists of the human androgen receptor (hAR). They inhibit AR-related gene expression and are human-relevant.

As a proof-of-principle, we demonstrate that one of these BAs suppresses tumor progression and potentiates the efficacy of anti-PD-1 treatment in an AR-dependent manner. Our findings show that an approach combining bioinformatics, BA metabolomics, and microbial genetics can expand our knowledge of the microbiota metabolic potential and reveal an unexpected microbiota BA-AR interaction and its role in regulating host biology.

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